This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Memapsin 2 ([unreadable]-secretase) is the protease that initiates a cleavage on amyloid precursor protein leading to the production of A[unreadable] and the onset of Alzheimer's disease (AD). Reduction of in vivo A production is a major goal to the development of treatments for AD. With the cloning of memapsin 2, this protease has emerged as the main therapeutic target for AD. We propose here to explore immunization with memapsin 2 as a potential approach to reduce A[unreadable] production in the brain. We have demonstrated the feasibility of this approach in transgenic AD mice model using the ectodomain of memapsin 2. The following Aims are designed to establish an efficacious immunization procedure, to determine the minimum effective antigen, and to demonstrate the absence of autoimmune complications. The Specific Aims are: Aim 1: To establish efficacious protocol for memapsin 2 immunization using both young and aged AD transgenic mice, which will simulate the use of vaccination as a preventive approach and a therapy for AD patients, respectively. The milestones are significantly reduced A[unreadable] in the plasma and improved brain amyloid load and cognitive function. Aim 2: To study the cellular mechanism of inhibition of A[unreadable] production by memapsin 2 antibodies. Studies seek to investigate the cellular location and mechanism for the inhibition of A[unreadable] production by memapsin 2 antibodies using transfected cell lines. The second is to identify the effective epitopes of memapsin 2 for inhibiting A[unreadable] production in cells in order to achieve a minimal auto-immune response when applied in animals.